Interleukin-6 synthesis induced by prostaglandin E2:: Cross-talk regulation by protein kinase C

We previously showed that prostaglandin E-2 (PGE(2)) stimulates multiple intracellular signaling pathways as follows: by activation of adenylate cyclase; phosphoinositide (PI)-hydrolyzing phospholipase C and phosphatidylcholine (PC)-hydrolyzing phospholipase D; and by induction of Ca2+ influx in osteoblast-like MC3T3-E1 cells, In this study, we investigated the effect of PGE(2) on the synthesis of interleukin-6 (IL-6) and its regulatory mechanism in MC3T3-E1 cells, PGE(2) significantly stimulated IL-6 secretion in a dose-dependent manner in the range between 1 nmol/L and 10 mu mol/L, A23187, a calcium ionophore, or dibutyryl-cAMP significantly induced IL-6 secretion, The effect of a combination of A23187 and dibutyryl-cAMP on IL-6 secretion was additive, The depletion of extracellular Ca2+ by EGTA reduced the PGE(2)-induced IL-6 secretion, EP1 receptor antagonist inhibited the PGE(2)-induced IL-6 secretion, H-89, an inhibitor of cAMP-dependent protein kinase, decreased the PGE(2)-induced IL-6 secretion, EP2 receptor agonist alone stimulated IL-6 secretion, However, EP4 receptor antagonist had little effect on IL-6 secretion, Calphostin C, a specific inhibitor of protein kinase C (PKC), enhanced the secretion of IL-6 induced by PGE(2), The stimulative effect of PGE(2) on IL-6 secretion was significantly enhanced in PI(C downregulated MC3T3-E1 cells, Pertussis toxin enhanced PGE(2)-induced IL-6 secretion, These results strongly suggest that PGE(2) stimulates IL-6 synthesis through both Ca2+ mobilization from extracellular space,ia EP1 receptor and cAMP production via EP2 receptor in osteoblast-like cells, and that the PKC activation by PGE(2) itself regulates oversynthesis of IL-6. (C) 1998 by Elsevier Science Inc, All rights reserved.